The present invention relates to a series of thiazolidine derivatives which have anti-hypertensive activity, and which have been found to be especially useful in the treatment and prophylaxis of hypertension associated with obesity.
Hypertension (or elevated blood pressure) is a condition that can threaten life or can reduce the quality of life of sufferers. It is well established that a reduction in blood pressure can significantly reduce the risks of morbidity and mortality. Obesity has been shown conclusively to be a significant contributing factor in the development of hypertension, and hypertension has been observed much more frequently in obese individuals than in those of normal body weight. Hypertension of this type has also been shown to be a risk factor which may induce the development of coronary artery disease [Kennel, et el. Intern. Med. 67 48-59 (1967); Stamler et al. J. Amer. Med. Assoc. 240 1607-1610 (1978)]. Obesity-related hypertension is classified as essential hypertension. There are, however, many problems not yet solved about the mechanism of hypertension. In particular, although it has been shown that various factors, such as increases in the levels of body fluids, the behavior of the sympathetic nervous system and the existence of hyperinsulinemia, all may have some influence on the development of hypertension in obese individuals, the relative importance of these, and other, factors has been assessed, nor has the mechanism whereby they exert their influence. Recently, it has been shown that obese humans often exhibit increased insulin resistance, as well as hyperinsulinemia and glucose tolerance insufficiency. There have been several reports indicating that hyperinsulinemia and glucose tolerance insufficiency due to obesity may be important factors in the development of obesity-associated hypertension [see, for example, DeFronzo et al.: J. Clin. Invest., 62, 204-213 (1978); Modan et al.: J. Clin. Invest., 75, 809-817 (1985); Reaven & Hoffman: Lancet, 2, 435-436 (1987) Ferrannini et al.: N. Engl. J. Med., 317, 350-357 (1987)].
Accordingly, attempts have been made to cure or alleviate the condition of obese hypertensive patients by improving insulin resistance, and to find an effective therapeutic agent to achieve this.